Novel crysalline forms of tegaserod maleate

ABSTRACT

The present invention relates to novel crystalline forms of tegaserod maleate, to processes for their preparation and to pharmaceutical compositions containing them.

FIELD OF THE INVENTION

The present invention relates to novel crystalline forms of tegaserodmaleate, to processes for their preparation and to pharmaceuticalcompositions containing them.

BACKGROUND OF THE INVENTION

EP Patent No. 0 442,378 describes, along with other compounds, thecompound (1)

or2-[(5-Methoxy-1H-indol-3-yl)methylene]-N-pentylhydrazinecarboximidamide,which has the generic name tegaserod and forms maleic acid salt(tagaserod maleate). Tegaserod and related compounds are serotonin5HT₄-receptor partial agonist and useful in the treatment of irritablebowel syndrome and other utilities as described in EP Patent No. 0442,378.

Crystalline forms of tegaserod maleate have not been reported in theliterature and also, the preparation of tegaserod maleate has not beendescribed. So, there is a need for stable polymorphs of tegaserodmaleate for better pharmaceutical preparations.

It has now been discovered that tegaserod maleate can be prepared infour different crystalline forms.

Thus the object of the present invention is to provide stable novelcrystalline forms of tegaserod maleate, processes for preparing theseforms and pharmaceutical compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a novelcrystalline form of tegaserod maleate, designated as Form I,characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 5.3, 5.9, 6.4, 10.7, 16.1 and 26.8 degrees.FIG. 1 shows typical Form I x-ray powder diffraction pattern.

In accordance with the present invention, a process is provided forpreparation of tegaserod maleate Form I. In this process, maleic acid isadded to a solution of tegaserod free base in acetone and tegaserodmaleate Form I is isolated from the mixture. Tegaserod maleate Form Imay be isolated by usual techniques like cooling, partial removal of thesolvent from the solution, adding an anti-solvent.

In accordance with the present invention, an alternative process isprovided for preparation of tegaserod maleate Form I. According to thisprocess, tegaserod maleate is mixed with acetone and collectingtegaserod maleate Form I from the mixture by filtration. In this processany of the crystalline forms of tegaserod maleate may be used.

In accordance with the present invention, there is provided a novelcrystalline form of tegaserod maleate, designated as Form II,characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 5.3, 6.4, 6.9, 7.8, 8.7, 10.2, 10.8, 15.5,16.8, 17.0, 19.5, 21.2, 21.7, 22.7 and 25.2 degrees. FIG. 2 showstypical Form II x-ray powder diffraction pattern.

In accordance with the present invention, a process is provided forpreparation of tegaserod maleate Form II. In this process, tegaserodmaleate is dissolved in methanol and tegaserod maleate Form II isprecipitated from the solution by adding acetonitrile. In this processany of the crystalline forms of tegaserod maleate may be used may beused to prepare the solution in methanol.

In accordance with the present invention, there is provided a novelcrystalline form of tegaserod maleate, designated as Form III,characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 7.0, 7.9, 8.7, 10.2, 15.6, 15.9, 17.0, 19.5,25.3 and 27.1 degrees. FIG. 3 shows typical Form III x-ray powderdiffraction pattern.

In accordance with the present invention, a process is provided forpreparation of tegaserod maleate Form III. In this process, maleic acidis added to a solution of tegaserod free base in methanol and thecontents are maintained for about 30 minutes at about 20° C. to 25° C.and then the crystals are collected by filtration.

In accordance with the present invention, another process is providedfor preparation of tegaserod maleate Form III. According to thisprocess, tegaserod maleate is dissolved in methanol and the solution ismaintained for about 30 minutes at about 20° C. to 25° C. and thentegaserod maleate Form III crystals are collected by filtration.

In accordance with the present invention, there is provided a novelcrystalline form of tegaserod maleate, designated as Form IV,characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 6.9, 8.0, 10.3, 16.5, 19.6, 20.4, 20.9, 22.0,23.2, 25.4, 28.0 and 28.7 degrees. FIG. 4 shows typical Form IV x-raypowder diffraction pattern.

In accordance with the present invention, a process is provided forpreparation of tegaserod maleate Form IV. In this process, maleic acidis added to a solution of tegaserod free base in methanol and tegaserodmaleate Form IV is precipitated by adding methylene dichloride orisopropyl alcohol.

Tegaserod free base used in the above processes may be obtained by theprocedures described in EP Patent No. 0 442,378.

In accordance with the present invention, there is provided apharmaceutical composition comprising crystalline form of tegaserodmaleate and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a x-ray powder diffraction pattern of tegaserod maleate FormI.

FIG. 2 is a x-ray powder diffraction pattern of tegaserod maleate FormII.

FIG. 3 is a x-ray powder diffraction pattern of tegaserod maleate FormIII.

FIG. 4 is a x-ray powder diffraction pattern of tegaserod maleate FormIV.

x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-raypowder diffractometer having a copper-Kα radiation.

The following examples further illustrate the invention.

EXAMPLE 1

Tegaserod free base (10 gm) is dissolved in acetone (100 ml). Maleicacid (4 gm) is added to the solution and the contents are maintained for1 hour at 25° C. The separated solid is filtered to give 12.5 gm oftegaserod maleate Form I.

EXAMPLE 2

Tegaserod maleate Form II (5 gm) and acetone (70 ml) are mixed andrefluxed for 1 hour and cooled to 25° C. and filtered to give 4.8 gm oftegaserod maleate Form I.

EXAMPLE 3

Tegaserod maleate Form I (10 gm) is dissolved in methanol (100 ml).Acetonitrile (150 ml) is added to the solution and the contents areheated to reflux. The contents are then cooled to 25° C. and maintainedfor 30 minutes. The separated crystals are collected by filtration togive 9 gm of tegaserod maleate Form II.

EXAMPLE 4

Tegaserod free base (10 gm) is dissolved in methanol (100 ml) and maleicacid (4 gm) is added to the solution. Then the contents are maintainedfor 30 minutes at 25° C. Then the separated solid is filtered to give 13gm of tegaserod maleate Form III.

EXAMPLE 5

Tegaserod maleate (5 gm) is dissolved in methanol (50 ml) and thesolution is maintained at 25° C. for 30 minutes. The separated crystalsare collected by filtration to give 4.8 gm of tegaserod maleate FormIII.

EXAMPLE 6

Tegaserod free base (10 gm) is dissolved in methanol (50 ml), maleicacid (4 gm) is added and the contents are refluxed for 30 minutes andthen the resulting solution is cooled to 25° C. Methylene dichloride(200 ml) is added and the contents are maintained for 30 minutes at 25°C. The separated solid is collected by filtration to give 13 gm oftegaserod maleate Form IV.

EXAMPLE 7

Maleic acid (4 gm) is added to a solution of tegaserod free base (10 gm)in methanol (50 ml). The contents are maintained for 30 minutes at 25°C. and isopropyl alcohol (150 ml) is mixed and contents are maintainedfor 30 minutes at 25° C. The separated solid is collected by filtrationto give 12.5 gm of tegaserod maleate Form IV.

1. A crystalline tegaserod maleate Form I, characterized by an x-raypowder diffraction pattern having peaks expressed as 2θ at about 5.3,5.9, 6.4, 10.7, 16.1 and 26.8 degrees.
 2. A crystalline tegaserodmaleate Form I as defined in claim 1, further characterized by an x-raypowder diffraction pattern as shown in FIG.
 1. 3. A process forpreparing tegaserod maleate Form I as defined in claim 1, whichcomprises: a) adding maleic acid to a solution of tegaserod free base inacetone; and b) Isolating tegaserod maleate Form I.
 4. A process ofpreparing tegaserod maleate Form I as defined in claim 1, whichcomprises mixing tegaserod maleate and acetone and collecting tegaserodmaleate Form I by filtration.
 5. A crystalline tegaserod maleate FormII, characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 5.3, 6.4, 6.9, 7.8, 8.7, 10.2, 10.8, 15.5,16.8, 17.0, 19.5, 21.2, 21.7, 22.7 and 25.2 degrees.
 6. A crystallinetegaserod maleate Form II as defined in claim 5, further characterizedby an x-ray powder diffraction pattern as shown in FIG.
 2. 7. A processfor preparing tegaserod maleate Form II as defined in claim 5, whichcomprises: a) dissolving tegaserod maleate in methanol; and b)precipitating tegaserod maleate Form II from the solution by mixing withacetonitrile;
 8. A crystalline tegaserod maleate Form III, characterizedby an x-ray powder diffraction pattern having peaks expressed as 2θ atabout 7.0, 7.9, 8.7, 10.2, 15.6, 15.9, 17.0, 19.5, 25.3 and 27.1degrees.
 9. A crystalline tegaserod maleate Form III as defined in claim8, further characterized by an x-ray powder diffraction pattern as shownin FIG.
 3. 10. A process for preparing tegaserod maleate Form III asdefined in claim 8, which comprises: a) mixing maleic acid and asolution of tegaserod free base in methanol; and b) collecting the solidseparated by filtration.
 11. A process for preparing tegaserod maleateForm III as defined in claim 8, which comprises; a) dissolving tegaserodmaleate in methanol; b) maintaining for about 30 minutes at about 20° C.to 25° C. to produce a solid; and c) collecting the solid by filtration.12. A crystalline tegaserod maleate Form IV, characterized by an x-raypowder diffraction pattern having peaks expressed as 2θ at about 6.9,8.0, 10.3, 16.5, 19.6, 20.4, 20.9, 22.0, 23.2, 25.4, 28.0 and 28.7degrees.
 13. A crystalline tegaserod maleate Form IV as defined in claim12, further characterized by an x-ray powder diffraction pattern asshown in FIG.
 4. 14. A process for preparation of tegaserod maleate FormIV as defined in claim 12, which comprises: a) mixing maleic acid and asolution of tegaserod free base in methanol; and b) precipitatingtegaserod maleate Form IV by mixing with methylene dichloride orisopropyl alcohol.
 15. A pharmaceutical composition comprising acrystalline form of tegaserod maleate and a pharmaceutically acceptablecarrier.
 16. A pharmaceutical composition as defined in claim 15,wherein the crystalline form is the tegaserod maleate Form I of claim 1.17. A pharmaceutical composition as defined in claim 15, wherein thecrystalline form is the tegaserod maleate Form II of claim
 5. 18. Apharmaceutical composition as defined in claim 15, wherein thecrystalline form is the tegaserod maleate Form III of claim
 8. 19. Apharmaceutical composition as defined in claim 15, wherein thecrystalline form is the tegaserod maleate Form IV of claim 12.